The mortality rate of ovarian cancer is the highest among all gynecological malignancies [1]. Therapeutic strategies consist of platinum-based chemotherapy, targeted therapy (anti-angiogenic agents and PARP inhibitors) and immunotherapy [2]. Cisplatin (cis-[Pt(NH3)2Cl2], CDDP) is the most frequently used platinum drug for ovarian cancer [3]. Most patients initially respond to CDDP, but drug resistance emerged after multiple relapses [4]. CDDP mediates its anticancer effects through Pt-DNA adducts induced replication inhibition and apoptosis induction [5]. DNA damage tolerance and repair machinery are the main causes of CDDP resistance.

To overcome the clinical limitations, structure perturbations are made to the framework of approved platinum drugs [6]. Among multifarious designs, Pt(II) complexes bearing a different amine or N-heterocyclic ligand with a general formula of cis-[Pt(NH3)LCl2] stand out as promising CDDP-like anticancer agents. Picoplatin (cis-[Pt(NH3)(2-picoline)Cl2]) and JM-118 (cis-[Pt(NH3)(cyclohexylamine)Cl2]) are the typical representatives (Fig. 1). In Phase I-II trials, picoplatin displayed a promising activity and improved safety profile in ovarian, lung and colon cancer [7]. Satraplatin (Fig. 1) and its active metabolite JM-118 showed preclinical anticancer activity in prostate, breast and lung cancer, including several CDDP-resistant cell lines [8].

Ferroptosis is a newly identified form of regulated cell death characterized by iron-dependent lipid peroxidation [9]. Regulation of iron metabolism and lipid peroxidation signaling is closely involved in ferroptosis [10]. SLC7A11 is a substrate-specific subunit of system xc−, importing cystine for glutathione biosynthesis to protect cells against ferroptosis [11]. Ferroptosis inducers erastin and sorafenib have been shown to block the activity of system xc−, leading to ferroptotic cell death [12]. Glutathione Peroxidase 4 (GPX4) is recognized as a central repressor of ferroptosis, which utilizes reduced glutathione to degrade lipid hydroperoxides [13]. GPX4 inhibition can enhance lipid peroxidation and result in ferroptosis [14]. CDDP induced ferroptosis through glutathione depletion and GPX4 inactivation in non-small lung cancer and colorectal cancer [15]. Since apoptosis evasion is considered as the major reason for drug resistant, ferroptosis inducers had great potential to become a promising approach in anticancer therapy [16].

Among heterocyclic compounds, quinoline derivatives draw great attention in coordination chemistry due to the metal-binding ability along with a variety of biological effects [17]. In this study, we present the synthesis and characterization of a quinoline derivative based Pt(II) complex PtQ. PtQ displayed certain cytotoxicity to a variety of human cancer cell lines. PtQ inhibited the proliferation of ovarian cancer and induced ferroptosis by inactivating SLC7A11/GPX4 signal axis. PtQ caused DNA single strand breaks and PARP1 inhibition which reduced DNA damage response resulting in a different anticancer mechanism from CDDP. Most platinum complexes have been designed to optimize the Pt-DNA interaction and apoptosis induction. However, apoptosis evasion and enhancing DNA damage repair result in therapeutic resistance to platinum-based drugs. Our study breaks the stereotype of traditional platinum-based drugs and proves that PtQ does not induce apoptosis but ferroptosis in ovarian cancer, which broadens our vision in the anticancer mechanism of CDDP-like analogs.